Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as the collagenases, stromelysins, gelatinases and matrilysin (known as "matrix metalloproteinases", and herein referred to as MMPs) are considered potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. It has been found that hydroxamic acid MMP inhibitors can also inhibit the production of the cytokine tumour necrosis factor ("TNF"). Compounds which inhibit the production or action of TNF are considered potentially useful for the treatment or prophylaxis of many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, rheumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive monoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury.
Metalloproteinases are characterised by the presence in the structure of a zinc(II) ionic site. It is now known that there exists a range of metalloproteinase enzymes that includes fibroblast collagenase (Type 1), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, stromelysin-2 and PUMP-1. Many known MMP inhibitors are peptide derivatives, based on naturally occuring amino acids, and are analogues of the cleavage site in the collagen molecule. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually have a functional group capable of binding to the zinc (II) site in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, sulphydryl, and oxygenated phosphorus (eg phosphinic acid and phosphonamidate including aminophosphonic acid) groups.
Two known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group and a carboxylic group respectively as their zinc binding groups. With a few exceptions, such known MMPs may be represented by the structural formula (A) ##STR2## in which X is the zinc binding hydroxamic acid (--CONHOH) or carboxylic acid (--COOH) group and the groups R.sub.1 to R.sub.5 are variable in accordance with the specific prior art disclosures of such compounds.
A particular class of known MMP inhibitors is characterised by the presence of an allyl group in the R.sub.1 position. Such compounds are disclosed, for example in WO 94/21625. That publication states that the preferred stereochemical configuration at the carbon atom carrying the allyl group is S and at the carbon atom carrying the R.sub.2 group is R. It also states that the disclosed MMP inhibitors may be prepared by coupling an acid of formula (B) or an activated derivative thereof with an amine of formula (C): ##STR3## wherein R.sub.2 -R.sub.5 are as defined in the publication, and R.sub.6 represents an alkyl (eg t-butyl) or benzyl group, and if desired then converting the --COOR.sub.6 group to a hydroxamic acid group.